Elsevier

The Lancet

Volume 389, Issue 10064, 7–13 January 2017, Pages 67-76
The Lancet

Articles
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial

https://doi.org/10.1016/S0140-6736(16)32455-2Get rights and content

Summary

Background

First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.

Methods

For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.

Findings

Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.

Interpretation

Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.

Funding

F Hoffmann-La Roche, Genentech.

Introduction

Urothelial cancer is an aggressive malignancy associated with about 165 084 of global deaths annually and a 5 year survival of about 5% in the metastatic setting.1, 2 Cisplatin-based chemotherapy, a first-line treatment standard, provides overall survival benefit;3 however, up to two-thirds of patients are ineligible4 due to impaired performance status or comorbidities (eg, renal dysfunction). Treatment alternatives include carboplatin-based combinations and single-drug chemotherapy5, 6, 7, 8 but are associated with shorter overall survival.9 In clinical practice, many patients do not receive systemic chemotherapy and are offered supportive care,5, 6, 10 further underscoring the need for more efficacious and tolerable treatments in cisplatin-ineligible patients.10, 11

Atezolizumab is a humanised engineered immunoglobulin G1 monoclonal antibody that inhibits binding of programmed death-ligand 1 (PD-L1) to receptors programmed death-1 (PD-1) and B7-1, thereby restoring anti-cancer T-cell activity and reinvigorating suppressed immune cells.12, 13 Atezolizumab has shown efficacy and a tolerable safety profile in a range of cancers, including locally advanced or metastatic urothelial cancer.12, 13, 14, 15, 16 In the IMvigor210 cohort of patients who progressed during or following platinum-based treatment, atezolizumab conferred significant clinical benefit,16 leading to accelerated regulatory approval, and several biomarkers associated with response were identified.16 In this Article, we present clinical data from the first-line cisplatin-ineligible IMvigor210 cohort—the first report of an anti-PD-L1/PD-1 checkpoint inhibitor in this setting—along with exploratory analyses to validate biomarker correlates of clinical outcomes.

Research in context

Evidence before this study

We searched PubMed for phase 3 clinical trials on advanced urothelial carcinoma published in English between Jan 1, 2005, and Jan 1, 2014, using the MeSH search terms “advanced” AND “bladder cancer”, “urothelial carcinoma”, “transitional cell carcinoma”. We identified 17 articles. We examined the articles specific to treatment of patients in the first-line setting, along with international congress presentations during the time period. We identified an unmet clinical need for effective and tolerable approaches to the treatment of patients with baseline characteristics that rendered them ineligible for cisplatin-based chemotherapy. No such treatments seemed to exist or be approved by the US Food and Drug Administration, European Medicines Agency, or related agencies, and the cytotoxic drugs commonly used in this population were consistently associated with toxicity and poor overall survival despite treatment.

Added value of this study

In this study, the humanised monoclonal anti-programmed death-ligand 1 antibody atezolizumab was assessed in patients with previously untreated, locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy. The original trial design for this study was focused on patients with disease progression during or after platinum-based chemotherapy and an exploratory cohort of first-line cisplatin-ineligible patients; however, in view of the potential for benefit in the first-line setting, the exploratory cohort was expanded to about 100 patients, using similar statistical assumptions. Objective responses by independent assessment according to Response Evaluation Criteria In Solid Tumors version 1.1 were durable, with 70% of patients continuing to respond after a median follow-up duration of almost 1·5 years. Overall survival also seemed to surpass historical rates, although differences in patient populations between studies, among other factors, complicate comparison. Atezolizumab also generally seemed to be safe and well tolerated in a patient population heavily dominated by renal insufficiency. Exploratory analyses to improve the understanding of the immune biology of atezolizumab efficacy identified correlates of response and survival including The Cancer Genome Atlas subtype and mutation load, which warrant further study as potential biomarkers for this drug in metastatic urothelial cancer.

Implications of all the available evidence

Cisplatin-based chemotherapy is the preferred first-line treatment for metastatic urothelial cancer and the only treatment shown to improve survival in patients with previously untreated disease. However, only a minority of patients with metastatic urothelial cancer receive first-line treatment with cisplatin-based chemotherapy. The population of patients who are ineligible for cisplatin has been under-represented in clinical studies in the past 30 years and as a result, these patients have poor outcomes. Atezolizumab shows potential as a first-line treatment option for these patients. Furthermore, biomarker data validate reports of this drug in the platinum-treated setting that linked intrinsic The Cancer Genome Atlas subtypes and mutation load with immunotherapy response.

Section snippets

Study design and patients

IMvigor210 was a multicentre, single-arm, phase 2 trial that investigated efficacy and safety of atezolizumab in metastatic urothelial cancer. This trial was done in 47 academic medical centres and community oncology practices across seven countries in North America and Europe. The protocol (appendix) was approved by the institutional review boards or independent ethics committees at each participating centre. All patients provided written informed consent before study entry. The study was done

Results

Between June 9, 2014, and March 30, 2015, we screened 167 patients and enrolled 123 of them; four of the enrolled patients subsequently did not meet eligibility criteria and did not receive the study drug atezolizumab (figure 1). 119 patients received one or more doses of atezolizumab. 102 (86%) patients discontinued treatment, either because of disease progression (n=77), patient withdrawal (n=12), an adverse event (n=11), or other reasons (n=2). At time of data cutoff (median follow-up was

Discussion

In this single-arm, phase 2 study, atezolizumab is the first anti-PD-L1/PD-1 drug to show durable responses with a tolerable safety profile in untreated, cisplatin-ineligible, metastatic, urothelial cancer. Objective responses occurred across all PD-L1 subgroups and identified prognostic subgroups, with high complete response rates relative to previous chemotherapy trials.9 With 17·2 months of median follow-up, median response duration had not been reached in all patients or in any of these

References (30)

  • PJ Loehrer et al.

    A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study

    J Clin Oncol

    (1992)
  • MD Galsky et al.

    Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy

    J Clin Oncol

    (2011)
  • Clinical practice guidelines in oncology: bladder cancer. Version 2

  • A Necchi et al.

    Efficacy and safety of gemcitabine plus either taxane or carboplatin in the first-line setting of metastatic urothelial carcinoma: a systematic review and meta-analysis

    Clin Genitourin Cancer

    (2016)
  • M De Santis et al.

    Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986

    J Clin Oncol

    (2012)
  • Cited by (1628)

    View all citing articles on Scopus

    IMvigor210 Study Group members listed in the appendix

    View full text